The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The present invention relates to 3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one derivatives which inhibit the activity of activin receptor like kinase (ALK-1; ALK-2, ALK-5). The compounds of this invention are therefore useful in treating diseases such as cancer.
The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
ALK5 is a synonym of TGFbetaR1.
ALK1 inhibitors inhibit neovascularization. ALK1 inhibitors are useful in all diseases where neovascularization is involved, such as cancer, rheumatoid arthritis and diseases of the eye. They are useful for the treatment of age-related macular degeneration and similar ocular disorders (WO 2013/04551). ALK2 inhibitors are useful for the treatment of progressively debilitating muscoskeletal disease fibrodysplasia ossificans progressive (FOP). See C. E. Sanvitale et al PLOS ONE, April 2013, Volume 8, issue 4, e62721. Methods for evaluating responsiveness of a subject having cancer to treatment with an ALK1 antagonist are described in WO 2014/055869 A1. WO 2014/141118 A1 relates to imidazo[4,5-c]quinoline derivatives and their use in the treatment of diseases mediated by kinases such as PI3 kinase or ALK1. The compounds described in WO 2014/141118 A1 can be used for the treatment of cancer, inflammation, angiogensis related disorders and bacterial infections.
R. S. Bhatt et al. describe in Clin. Cancer Res. 2014; 20:2838-2845: Two ALK1 inhibitors have entered clinical trials, ACE-041 (dalantercept; Acceleron Pharma) and PF-03446962 (Pfizer).
M. Petersen et al. describe in Kidney International (2008) 73, 705-715 the use of GW788388, an inhibitor of the TGF-β type I and II receptor kinases, for the treatment of renal fibrosis.
WO 2014/151871 A2 discloses pyrimidine derivatives as ALK2 inhibitors for the treatment of cancer, such as a myeloproliferative disorder, a lymphoma or a solid tumor, moreover for the treatment of anemia of chronic disease, anemia of chronic inflammation, anemia of cancer or fibrodysplasia ossificans progressive.
Members of the transforming growth factor-β (TGF-β) superfamily, including TGF-β, activin, nodal, and bone morphogenetic proteins (BMPs), are multifunctional cytokines that regulate a wide range of cellular responses, including cell proliferation, differentiation, adhesion, migration, and apoptosis.(1,2) TGF-β and related proteins transduce signals through two distinct serine/threonine kinase receptors, termed type I and type II.(3,4) The type II receptors are the primary ligand binding receptors at the cell surface and contain constitutively active kinases, which phosphorylate corresponding type I receptors. Seven type I receptors termed activin receptor-like kinase (ALK) 1 through 7 have been identified in mammals. ALK-4, ALK-5, and ALK-7 are structurally highly related to each other and transduce similar, though not identical, intracellular signals.(5) TGF-β and activin bind to ALK-5 (type I TGF-β receptor; TβR-I) and ALK-4 (type IB activin receptor; ActR-IB), respectively. Signals for nodal proteins are transduced by ALK-4 as well as ALK-7.(6) In contrast, ALK-1, -2, -3 and -6 transmit signals similar to each other's. BMPs bind to ALK-2, ALK-3 (type IA BMP receptor; BMPR-IA), and ALK-6 (type IB BMP receptor; BMPR-IB), whereas ALK-1 is highly expressed in endothelial cells and binds to TGF-β in these cells.(7) 
Upon activation by type II receptors, type I receptor ALKs transduce intracellular signals through various proteins, of which Smad proteins are the major signaling molecules for TGF-β superfamily proteins.(3,5) Eight different Smad proteins have been identified in mammals, and are classified into three groups: receptor-regulated Smads (R-Smads), common-partner Smads (Co-Smads), and inhibitory Smads (I-Smads). Smad2 and Smad3 are R-Smads activated by TGF-β/activin/nodal receptors ALK-4, -5, and -7, whereas Smad1, Smad5, and Smad8 are BMP-specific R-Smads.(5) Smad4 is the Co-Smad shared by signaling pathways for TGF-β and activin and those for BMPs. Smad6 and Smad7 are I-Smads in mammals; Smad6 preferentially suppresses BMP signaling, whereas Smad7 inhibits both BMP and TGF-β signaling.
The roles of TGF-β in cancer biology are complex; TGF-β can suppress or promote tumor growth depending on the type of cancer. The ability of TGF-β to potently inhibit the proliferation of epithelial, endothelial, and hematopoietic cell lineages is central to its tumor-suppressive effects. However, as tumors evolve, they often become refractory to TGF-β-mediated growth inhibition and overexpress TGF-β, which induces epithelial-to-mesenchymal transition (EMT) of tumor cells and facilitates immunosuppression, extracellular matrix deposition, and angiogenesis. It was recently reported that inhibition of autocrine TGF-β signaling in carcinoma cells reduces cell invasiveness and tumor metastasis, and that these effects of TGF-β are closely associated with the ability of TGF-β to induce EMT and stimulate cell migration.(8,9) The TGF-β signaling pathway has correspondingly become an attractive target for drug development in the field of oncology.(10,11) 
G. J. Inman et al., Molecular Pharmacology Jul. 1, 2002 vol. 62 no. 1, 65-74, characterized a small molecule inhibitor (SB-431542) that was identified as an inhibitor of activin receptor-like kinase (ALK)5 (the TGF-β type I receptor). They demonstrated that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are very highly related to ALK5 in their kinase domains.